Pharmacokinetics of crizotinib in NSCLC patients

Abstract

Introduction: For a subpopulation of NSCLC patients genetic rearrangement of the anaplastic lymphoma kinase (ALK) was found as driver mutation, which can be targeted by the selective inhibitor crizotinib.

Areas covered: This article presents an overview of the clinical studies that provided the characterization of the pharmacokinetic parameters for the administration of crizotinib to cancer patients and the factors influencing the clinical profiles of this drug.

Expert opinion: Crizotinib is administered orally as a capsule and clinical studies indicated 250 mg crizotinib BID continuously as the maximal tolerated dose in cancer patients. Bioavailability is ∼ 40% and pharmacokinetic parameters are influenced by food only to a minor degree. This dose of the drug corresponds to a significant inhibition of the mutated ALK, retards tumor growth and achieves clinical responses in the majority of patients. Crizotinib lactam is the single metabolite with minor inhibitory activity for the ALK fusion protein. Metabolization is executed mainly by CYP3A4/5 and is modulated by other drugs interacting with this cytochrome oxidase. Despite the one-fits-all approach in administration of crizotinib at a fixed dose the pharmacokinetic parameters indicate a stable steady state upon continuous administration, which achieves sufficient inhibition of the ALK drug target.

Keywords:

• anaplastic lymphoma kinase
• crizotinib
• NSCLC
• pharmacokinetics
• tyrosine kinase inhibitor

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.